Oligosaccharide Aldonic Acids and Their Topical Use

ABSTRACT

Methods for using compositions comprising oligosaccharide aldonic acids for general care, as well as for treatment and prevention, of various cosmetic conditions and dermatological disorders, including those associated with intrinsic and/or extrinsic aging, as well as with changes or damage caused by extrinsic factors; general care, as well as treatment and prevention of diseases and conditions, of the oral, and vaginal mucosa; for general oral care, as well as treatment and prevention of oral and gum diseases; and for wound healing of the skin. Methods may comprise using compositions comprising oligosaccharide aldonic acids and additional cosmetic, pharmaceutical or other topical agents to enhance or create synergetic effects.

This application is a divisional application and claims the benefit ofU.S. application Ser. No. 11/872,459, filed Oct. 15, 2007, which is adivisional of U.S. application Ser. No. 10/811,998, filed Mar. 30, 2004,which is a continuation of U.S. application Ser. No. 09/987,023, filedNov. 13, 2001, now U.S. Pat. No. 6,740,327, which is a continuation ofU.S. application Ser. No. 09/487,228, filed Jan. 19, 2000, now U.S. Pat.No. 6,335,023, which claims priority from U.S. provisional applicationSer. No. 60/141,264, filed Jun. 30, 1999.

FIELD OF THE INVENTION

This application relates to compositions comprising oligosaccharidealdonic acids and related compounds, and their use for cosmetic anddermatological indications, reducing and soothing mucosa and skinerythema, inflammation or reaction caused by internal or externalfactors, wound healing, and care of skin, hair, nail, and oral andvaginal mucosa, including the use for changes associated with intrinsicand extrinsic aging, and changes or damage caused by extrinsic factorssuch as sunlight, radiation, air pollution, wind, cold, heat, dampness,chemicals, smoke, and cigarette smoking.

BRIEF DESCRIPTION OF THE PRIOR ART

In our U.S. patent application Ser. No. 06/945,680, filed Dec. 23, 1986,entitled “Additives Enhancing Topical Actions of Therapeutic Agents,”and related applications, issuing, inter alia, as U.S. Pat. Nos.5,665,776, 5,389,677, and 5,422,370, we described and claimedcompositions for and methods of enhancing the therapeutic effect of acosmetic or pharmaceutical agent by using a hydroxyacid in combinationwith the agent. The generic structure of hydroxymonocarboxylic acidsdisclosed may appear similar to the one described herein foroligosaccharaide aldonic acids. The location of the R₂ molecule is anotable difference. This application disclosed that “when n=0 and m=1 ormore, the hydroxymonocarboxylic acid is also called aldonic acid. Thename comes from a carbohydrate, aldose, which may be oxidized to aldonicacid by the oxidation of the aldehyde group in aldose to the carboxylicgroup.” The application, however, does not disclose or suggest that acarbohydrate may be chemically linked to an aldonic acid. Thus, thisapplication does not disclose or suggest oligosaccharide aldonic acids.

In our related U.S. patent application Ser. No. 07/683,437, filed Apr.10, 1991, entitled “Compositions Comprising 2-Hydroxycarboxylic Acidsand Related Compounds, and Methods for Alleviating the Signs ofDermatological Aging,” and related applications, and issuing, interalia, as U.S. Pat. Nos. 5,547,988, 5,554,597, and 5,561,158, wedescribed and claimed the use of topical compositions containing a2-hydroxycarboxylic acid or related compound for use in alleviating orimproving the signs of aging, including the signs caused by intrinsicand extrinsic aging or extrinsic factors, of the skin, hair and nails.Among the many compounds disclosed in this application, lactobionicacid, an oligosaccharide aldonic acid, is listed as a useful relatedcompound.

We have now discovered that oligosaccharide aldonic acids and relatedcompounds, as a group, provide numerous benefits in the treatment andprevention of various cosmetic conditions and dermatological disorders,including those associated with intrinsic and extrinsic aging, as wellas changes and damage caused by extrinsic factors. Oligosaccharidealdonic acids and related compounds also provide numerous benefits inthe treatment of skin wounds; reducing or soothing erythema,inflammation or irritation; general care, as well as treatment andprevention of diseases and conditions, of the nasal, oral and vaginalmucosa; and general oral care and treatment and prevention of oral andgum diseases.

We have further discovered that oligosaccharide aldonic acids possessunexpected physicochemical properties, including binding with water andthe formation of a gel matrix with water. In addition, theoligosaccharaide aldonic acids disclosed herein are antioxidantsubstances. Moreover, beneficial effects from an oligosaccharaidealdonic acid within the skin, nail and hair are expected to includethose provided by glycosaminoglycans (GAGs). This is due to similaritiesin the basic chemical structure of oligosaccharaide aldonic acids andGAGs, and the fact that they both form a gel matrix with water.Exemplary beneficial effects and functions of GAGs inside the skinincludes (i) binding with polycations and cations, such as sodium andpotassium ions, to enhance water retention, and (ii) specificinteraction with collagen, elastin, fibronectin, laminin and otherproteins to stabilize the turgor of the skin.

SUMMARY OF THE INVENTION

Accordingly, it is an object of this invention to provide methods andcompositions which are useful in the treatment and prevention of certaincosmetic conditions and dermatological disorders, promote wound healing,and are useful for general care of skin, hair, nail, oral and vaginalmucosa, and oral and gum diseases.

We have now discovered that oligosaccharide aldonic acids haveprotective as well as healing effects for skin, hair, nail; oral, nasaland vaginal mucosa. The oligosaccharide aldonic acids includeglycerbionic acids, erythrobionic acids, threobionic acids, ribobionicacids, arabinobionic acids, xylobionic acids, lyxobionic acids,allobionic acids, altrobionic acids, glucobionic acids, mannobionicacids, gulobionic acids, idobionic acids, galactobionic acids,talobionic acids, alloheptobionic acids, altroheptobionic acids,glucoheptobionic acids, mannoheptobionic acids, guloheptobionic acids,idoheptobionic acids, galactoheptobionic acids and taloheptobionicacids.

Compositions comprising oligosaccharide aldonic acids are beneficial andeffective for general care, reducing and soothing mucosa and skinerythema, inflammation or reaction caused by internal or externalfactors, treatment and healing of skin, hair, nail; nasal, oral andvaginal mucosa including treatment, healing and prevention of cosmeticconditions and dermatological indications as well as cosmetic andclinical signs of changes associated with intrinsic aging, or thedamages caused by extrinsic factors as sunlight, radiations, airpollution, wind, cold, dampness, heat, chemicals, smoke, and cigarettesmoking.

General care, reducing and soothing mucosa and skin erythema,inflammation or irritation caused by internal or external factors,treatment and healing of skin, hair, nail; nasal, oral and vaginalmucosa, and treatment, healing and prevention of cosmetic conditions anddermatological indications as well as cosmetic and clinical signs ofchanges associated with intrinsic aging, or the damages caused byextrinsic factors as sunlight, radiations, air pollution, wind, cold,dampness, heat, chemicals, smoke, and cigarette smoking may includeblemished, irritated, inflammed, unhealthy, damaged or abnormal mucosa,skin, hair, nail, nostril, ear canal or vaginal conditions; oral or gumdisease; disturbed keratinization; defective syntheses or repair ofdermal components, and changes associated with intrinsic and extrinsicaging of skin, nail and hair. Those conditions and indications includedryness of the skin, nail and hair; xerosis; ichthyosis; palmar andplantar hyperkeratoses; uneven and rough surface of skin, nail and hair;dandruff; Darier's disease; lichen simplex chronicus; keratoses; acne;pseudofolliculitis barbae; eczema; psoriasis; pruritus; warts; herpes;age spots; lentigines; melasmas; blemished skin; mottled skin;hyperkeratoses; hyperpigmented skin; abnormal or diminished syntheses ofcollagen, glycosaminoglycans, proteoglycans and elastin as well asdiminished levels of such components in the dermis; cellulite; stretchmarks; skin lines; fine lines; wrinkles; thinning of skin, nail plateand hair; skin thickening due to elastosis of photoaging, loss orreduction of skin, nail and hair resiliency, elasticity andrecoilability; lack of skin, nail and hair lubricants and luster; dulland older-looking skin, nail and hair; fragility and splitting of nailand hair.

Oligosaccharide aldonic acids are also beneficial for wound healing ofskin; irritated or inflammed mucosa or skin; for skin lightening; forcleansing of skin, hair and nail; for conditioning of skin and nail; forprotection from extrinsic factors; for mouthwashes; for use asantioxidant agent, toner, cleanser, moisturizer, emollient, protectant,foundation makeup, beauty masks, face powders, rouge, cover up,lipsticks, eye makeup, dentifrices, mouthwashes, suntan preparation,soap preparation, and other topical preparations.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 1. OligosaccharaideAldonic Acids and Related Compounds

An oligosaccharide aldonic acid may be defined as an aldonic acid havinga carbohydrate chemically linked to the aldonic acid. The total numberof carbohydrate monomers including the aldonic acid itself ranges from 2to 10. The aldonic acid may be described as an oxidized form of acarbohydrate. For example, gluconic acid may be obtained from glucosethrough an oxidation of the aldehyde group to a carboxylic group.Although an oligosaccharide aldonic acid may consist of one to tenaldonic acid units, preferred compounds contain one aldonic acid unitand one to nine carbohydrate monomers. When the total number of thecarbohydrate monomers including the aldonic acid itself are 2, 3, 4, 5,6, 7, 8, 9 and 10, these oligosaccharide aldonic acids may berespectively called aldobionic acid, aldotrionic acid, aldotetraonicacid, aldopentaonic acid, aldohexaonic acid, aldoheptaonic acid,aldooctaonic acid, aldononaonic acid and aldodecaonic acid. The mostpreferred is aldobionic acid. If the name of a precursor oligosaccharideis known, such name may be utilized as a prefix. For example,lactobionic acid is derived from lactose, maltobionic acid from maltose,cellobionic acid from cellobiose, isomaltobionic acid from isomaltose,gentiobionic acid from gentiobiose and laminarabionic acid fromlaminarabiose. Alternatively, the name of a specific aldonic acid mayalso be used such as glycerbionic acid, erythrobionic acid, xylobionicacid, mannobionic acid and glucoheptabionic acid.

The smallest aldonic acid having three carbon atoms is glyceric acid,which is obtained from glyceraldehyde. A carbohydrate having one to ninemonomers may be chemically linked to one of the two hydroxyl groups at2nd or 3rd carbon position of glyceric acid to form an oligosaccharidealdonic acid. When one carbohydrate monomer is linked to glyceric acidthe compound may be called glycerbionic acid.

Erythronic acid and threonic acid, which have four carbon atoms, may beobtained respectively from erythrose and threose through an oxidationprocess. A carbohydrate having one to nine monomers may be chemicallylinked to one of the three hydroxyl groups at 2nd, 3rd or 4th carbonposition of the aldonic acid. When one carbohydrate monomer is attachedto the aldonic acid the resulting compound may be called erythrobionicacid or threobionic acid.

Ribonic acid, arabinoic acid, xylonic acid and lyxonic acid, which havefive carbon atoms, may be obtained respectively from ribose, arabinose,xylose and lyxose through an oxidation process. A carbohydrate havingone to nine monomers may be chemically linked to one of the fourhydroxyl groups at 2nd, 3rd, 4th or 5th carbon position of the aldonicacid. When one carbohydrate monomer is attached to the aldonic acid, theresulting compound may be called ribobionic acid, arabinobionic acid,xylobionic acid or lyxobionic acid.

Allonic acid, altronic acid, gluconic acid, mannonic acid, gulonic acid,idonic acid, galactonic acid and talonic acid, which have six carbonatoms, may be obtained respectively from allose, altrose, glucose,mannose, gulose, idose, galactose and talose through oxidation. Acarbohydrate having one to nine monomers may be chemically linked to oneof the five hydroxyl groups at 2nd, 3rd, 4th, 5th or 6th carbon positionof the aldonic acid. When one carbohydrate monomer is attached to thealdonic acid, the resulting compound may be called allobionic acid,altrobionic acid, glucobionic acid, mannobionic acid, gulobionic acid,idobionic acid, galactobionic acid or talobionic acid.

Alloheptonic acid, altroheptonic acid, glucoheptonic acid, mannoheptonicacid, guloheptonic acid, idoheptonic acid, galactoheptonic acid andtaloheptonic acid, which have seven carbon atoms, may be obtainedrespectively from alloheptose, altroheptose, glucoheptose, mannoheptose,guloheptose, idoheptose, galactoheptose and taloheptose throughoxidation. A carbohydrate having one to nine monomers may be chemicallylinked to one of the six hydroxyl groups at 2nd, 3rd, 4th, 5th, 6th or7th carbon position of the aldonic acid. When one carbohydrate monomeris attached to the aldonic acid, the resulting compound may be calledalloheptobionic acid, altroheptobionic acid, glucoheptobionic acid,mannoheptobionic acid, guloheptobionic acid, idoheptobionic acid,galactoheptobionic acid or taloheptobionic acid.

A common carbohydrate monomer such as glucose contains an aldehyde group(first carbon position) and five hydroxyl groups, whereas fructosecontains a keto group (at second carbon position) and five hydroxylgroups. Many carbohydrate monomers form a five (furanoside) or six(pyranoside) member ring between the aldehyde or keto group and one ofthe hydroxyl groups at 4th or 5th carbon position of the molecule. Anewly formed hydroxyl group (anomeric hydroxyl) at the originalfunctional group has two isomers: alpha or beta anomer, depending ondown or up of the hydroxyl position. A disaccharide is usually formedfrom two monosaccharides (carbohydrate monomers) by eliminating one moleof water between two anomeric hydroxyl groups (non-reducingdisaccharide) or between one anomeric hydroxyl of the second monomer andone of the hydroxyl in the first monomer (reducing disaccharide). Anon-reducing disaccharide such as sucrose formed from fructose andglucose can not be oxidized to an aldonic acid, whereas a reducingdisaccharide such as maltose formed from two glucose molecules can beoxidized to maltobionic acid. Oligosaccharides containing three to tenmonomers may be formed in the same manner as in that of disaccharides.As an alternative example, tetrasaccharides may also be formed from twodisaccharides.

Since the chemical link between two carbohydrate monomers can be atdifferent carbon positions, numerous different oligosaccharides may beformed. The same is true for oligosaccharide aldonic acids. For example,the disaccharides maltose and cellobiose are both formed from twoglucose molecules linked between the anomeric hydroxyl of the secondglucose and the hydroxyl at the 4^(th) carbon position of the firstglucose molecule. The only difference is that maltose is an alpha anomerand cellobiose is a beta anomer. The same is true when these twodisaccharides are oxidized to aldonic acids. The only difference betweenmaltobionic acid and cellobionic acid is that the former is an alpha andthe latter is a beta anomer.

Many disaccharides which may be converted to bionic acids includeglycerbioses, erythrobioses, threobioses, ribobioses, arabinobioses,xylobioses, lyxobioses, allobioses, altrobioses, glucobioses,mannobioses, gulobioses, idobioses, galactobioses, talobioses,alloheptobioses, altroheptobioses, glucoheptobioses, mannoheptobioses,guloheptobioses, idoheptobioses, galactoheptobioses, taloheptobioses,maltose, isomaltose, lactose, cellobiose, gentiobiose, laminaribiose,kojibiose, melibiose, nigerose, rutinose and sophorose. Bionic acids maybe obtained from these disaccharides by an oxidation process withhypoiodite, bromine water or enzyme.

In accordance with the present invention, the generic structure ofoligosaccharide aldonic acids may be represented as follows:

R₁ (CHOR₂)_(m) (CH₂)_(n)COOR₃

wherein:

R₁ and R₃ are independently H or an alkyl, aralkyl or aryl group ofsaturated or unsaturated, straight or branched chain or cyclic form,having 1 to 25 carbon atoms;

m is 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

n is 0, 1, 2 3, 4, 5, 6, 7, 8, or 9;

R₂ is independently selected from H or any carbohydrate having from 1 to9 monomers in each (CHOR₂), and at least one R₂ is a carbohydrate. Forexample, when m=5, one of the five R₂ may be a carbohydrate and theremaining four R₂ may be H;

H attached to carbon atom may be substituted by I, F, Cl, Br, NH₂,NHCOCH₃, SH, or alkyl, alkoxyl, aralkyl or aryl group of saturated orunsaturated, straight or branched chain or cyclic form, having from 1 to9 carbon atoms;

R₁, R₂, OR₂ or H may carry or be substituted with CHO, COON, sulfate,phosphate, nitrate, or lower alkoxyl having from 1 to 5 carbon atoms;

H of the OH group may be substituted by an acyl group having from 2 to25 carbon atoms, such as acetyl (CH₃CO), propanoyl (CH₃CH₂CO), octanoyl[CH₃(CH₂)₆CO], octadecanoyl [CH₃(CH₂)₁₆CO], eicosanoyl [CH₃(CH₂)₁₈CO],tetraeicosanoyl [CH₃(CH₂)₂₂CO] or benzoyl (C₆H₅CO) group.

Oligosaccharide aldonic acids according to the present invention may bepresent as isomeric D, L, DL or any other isomeric or non-isomeric form,saturated or unsaturated, straight or branched chain or cyclic form,free acid, ester, lactone, salt or partial salt form with organic orinorganic alkali.

The preferred oligosaccharide aldonic acids contain 2 to 6 carbohydratemonomers, and more preferred ones contain 2 to 3 carbohydrate monomers,and the most preferred oligosaccharide aldonic acids contain twocarbohydrate monomers. The most preferred oligosaccharide aldonic acidsmay be called bionic acids which contain two carbohydrate monomers. Inthe bionic acid, the chemical link between the two carbohydrate monomerscan be at any carbon position. The preferred link is between theanomeric carbon of the second monomer chemically bond to any positionother than the first carbon position of the first monomer. In addition,two anomeric isomers such as alpha and beta isomers can be formed whenthe second monomer is linked to the first monomer, and thereforenumerous different bionic acids may exist. For example, glucobionicacids include maltobionic acid and cellobionic acid.

As an example, chemical structures of some oligosaccharaide aldonicacids are depicted below:

Oligosaccharide aldonic acid lactones are usually obtained from theiraldonic acids by eliminating one mole of water through intramolecularcyclization between the carboxyl group and one of the hydroxyl groups.Common lactones consist of five or six member rings.

Examples of lactone form include lactobionolactone, maltobionolactone,isomaltobionolactone, cellobionolactone, chitobionolactone,gentiobionolactone, glucobionolactone, galactobionolactone,mannobionolactone, ribobionolactone, kojibionolactone, xylobionolactone,arabinobionolactone, nigerobionolactone, laminarabinobionolactone,maltotrionolactone, isomaltotrionolactone, chitotrionolactone,cellotrionolactone, gentiotrionolactone, maltotetraonolactone,cellotetraonolactone and chitotetraonolactone.

Examples of ester form include methyl lactobionate, ethyl lactobionate,propyl lactobionate, benzyl lactobionate, methyl maltobionate, ethylmaltobionate, propyl maltobionate, benzyl maltobionate, methylcellobionate, ethyl cellobionate, propyl cellobionate and benzylcellobionate.

Examples of acyl form include acetyl lactobionic acid, acetylmaltobionic acid and acetyl cellobionic acid.

Examples of both acyl and ester form include acetyl lactobionic acidmethyl, ethyl or propyl ester; acetyl maltobionic acid methyl, ethyl orpropyl ester; acetyl cellobionic acid methyl, ethyl or propyl ester.

On one embodiment of the inventions, the group of oligosaccharidealdonic acids and related compounds according to the invention are thegroup of compounds discussed herein, but excluding lactobionic acid. Inanother embodiment of the invention the group of oligosaccharide aldonicacids and related compounds according to the invention are the group ofcompounds discussed herein, but excluding lactobionic acid and salts,lactones, and thereof.

Oligosaccharide aldonic acids may be classified into groups accordingthe number of carbohydrate monomers such as aldobionic acid, aldotrionicacid, aldotetraonic acid, aldopentaonic acid, aldohexaonic acid,aldoheptaonic acid, aldooctaonic acid, aldononaonic acid andaldodecaonic acid. The preferred groups are aldobionic acid up toaldohexaonic acid, with more preferred groups of aldobionic acid up toaldotetraonic acid, and with most preferred groups being aldobionic acidand aldotrionic acid.

Many different aldobionic acids and aldotrionic acids exist due tovarious carbohydrate monomers and different linking positions betweentwo monomers. For example, even in the smallest molecule of glycerbionicacid (six carbon atoms) formed from glyceraldehyde (second monomer) andglyceric acid, there are two different glycerbionic acids; linking at2nd or 3rd carbon position of the glyceric acid. Glycerbionic acids alsoinclude various second monomers linked to glyceric acid at the 2nd or3rd carbon position. The second monomers include erythrose, threose,ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose,gulose, idose, galactose, talose, 6-deoxymannose, 2-deoxyaminoglucoseand fucose. Some representative oligosaccharide aldonic acids includethe following:

(i) Aldobionic Acids (Bionic Acids)

These bionic acids consist of one carbohydrate monomer linked to analdonic acid, and include glycerbionic acids, erythrobionic acids,threobionic acids, ribobionic acids, arabinobionic acids, xylobionicacids, lyxobionic acids, allobionic acids, altrobionic acids,glucobionic acids, mannobionic acids, gulobionic acids, idobionic acids,galactobionic acids, talobionic acids, alloheptobionic acids,altroheptobionic acids, glucoheptobionic acids, mannoheptobionic acids,guloheptobionic acids, idoheptobionic acids, galactoheptobionic acids,taloheptobionic acids, chitobionic acids, hyalobiouronic acids,hyalourobionic acids, chondrosines, chondrosinbionic acids,cellobiouronic acids, and cellourobionic acids.

As an example, glucobionic acids include lactobionic acid,isolactobionic acid, maltobionic acid, isomaltobionic acid, cellobionicacid, gentiobionic acid and laminarabionic acid. All these bionic acidsare formed from the same or a different carbohydrate monomer linked togluconic acid through a different or the same position. Otherindividually named bionic acids include melibionic acid, nigerobionicacid, rutinobionic acid, sophorobionic acid and kojibionic acid.

(ii) Aldotrionic Acids (Trionic Acids)

These trionic acids consist of two carbohydrate monomers linked jointlyor separately to an aldonic acid, and include glycertrionic acids,erythrotrionic acids, threotrionic acids, ribotrionic acids,arabinotrionic acids, xylotrionic acids, lyxotrionic acids, allotrionicacids, altrotrionic acids, glucotrionic acids, mannotrionic acids,gulotrionic acids, idotrionic acids, galactotrionic acids, talotrionicacids, alloheptotrionic acids, altroheptotrionic acids,glucoheptotrionic acids, mannoheptotrionic acids, guloheptotrionicacids, idoheptotrionic acids, galactoheptotrionic acids,taloheptotrionic acids, chitotrionic acids, hyalotriouronic acids,hyalourotrionic acids, chondrosintrionic acids, cellotriouronic acidsand cellourotrionic acids.

(iii) Other Oligosaccharide Aldonic Acids and Related Compounds

Aldonic acids with higher molecular weight may consist of three to ninecarbohydrate monomers linked jointly or separately to an aldonic acid,and include aldotetraonic acids, aldopentaonic acids, aldohexaonicacids, aldoheptaonic acids, aldooctaonic acids, aldononaonic acids andaldodecaonic acids. Miscellaneous or related aldonic acids include thosewhich are not readily represented or included in the above genericstructure, or which have additional functional groups in the molecules,such as a carbohydrate linked to an uronic acid, which may or may not berepresented by the above generic structure. A sulfate, phosphate,nitrate group, amino, acetamino group etc. may be substituted at H or OHsimilar to that of chitin, chitosan, hyaluronic acid, chodroitinsulfate, heparin, etc. to form substituted oligosaccharide aldonicacids.

2. Topical Uses of Oligosaccharide Aldonic Acids and Related Compounds

(i) Oligosaccharide Aldonic Acids and Related Compounds

Compositions comprising an oligosaccharide aldonic acid or relatedcompound described herein have numerous beneficial effects and a broadrange of uses. These compositions can comprise one or more than oneoligosaccharide aldonic acid or related compound.

According to one aspect of the invention, these compositions may be usedfor general care; moisturizing; dry skin; reducing irritation orinflammation of or soothing skin and mucosa or treatment or preventionof skin or mucosa irritation or inflammation caused by external factors,such as chemicals; skin smoothing and itchy skin; as well as fortreatment and prevention, of various cosmetic conditions anddermatological disorders, including those associated with intrinsicand/or extrinsic aging, as well as with changes or damage caused byextrinsic factors. In a preferred embodiment, the compositions may beused for skin, hair and nail changes associated with intrinsic and/orextrinsic aging, and changes or damage caused by extrinsic factors suchas sunlight, radiations, air pollution, wind, cold, dampness, heat,chemicals, smoke, and cigarette smoking. In addition, the compositionsof the present invention may be used to treat skin wounds, for examplein aiding the healing of skin cuts, tears, lacerations, burns,punctures, and other wounds.

According to another aspect of the invention, these compositions may beused for general care, as well as treatment and prevention of diseasesand conditions, of the oral, nasal and vaginal mucosa. For example, thecompositions may be used for care and treatment of blemished, unhealthy,damaged, irritated, or abnormal oral, nasal or vaginal mucosa, and gumdiseases.

According to still another aspect of the invention, these compositionmay be used for general oral care, as well as treatment and preventionof oral and gum diseases.

With respect to age associated skin changes, the underlying bases ofthese changes is described in U.S. Pat. No. 4,603,146 (Kligman). Inparticular, the underlying causes of skin changes associated with agingcan be more easily understood in view of the following summary of thechanges in the epidermis and dermis as aging progresses.

With increasing age and exposure of human to sun and other environmentaltraumas, cells divide at a slower rate (decreased capacity to renewthemselves). They show marked irregularities in size, shape and stainingproperties; orderliness (polarity) from below to above is lost. Thethickness of the epidermis decreases (atrophy). The horny layer whichcomprises the barrier against water loss and penetration of chemicalsbecomes abnormal due to the shedding (exfoliation) of cells in largegroup or clusters instead of as individual cells, resulting inroughness, scaling and dryness. There is loss of the orderlytransformation of living epithelial cells into cornified dead cellswhich are shed at the surface, that is, differentiation is impaired.Aberrant differentiation results in numerous foci of abnormal epithelialgrowths or tumors, the most frequent and important of which are actinickeratoses. After many years these can transform into frank skin cancerscalled basal cell and squamous cell cancers. Pigment producing cells(melanocytes) can also become altered forming flat, dark growths(lentigo melanoma) which may progress to malignant melanomas.

The cells which make the fibers of the dermis become smaller and sparserwith increasing age, usually in sun-damaged facial skin. There is agreat loss of collagen fibers resulting in looseness and easystretchability of the skin; elastic fibers become abnormal so that theskin does not promptly snap back after being stretched. Since thefibrous components comprise more than 90% of the bulk of skin of which95% is collagen, the degradation of these fibers, especially collagen,is mainly responsible for wrinkling, laxness and loss of elasticity.

Additionally, small blood vessels become thin walled, dilated and oftenruptured. Vascular supply thereby becomes compromised.

The signs of nail and hair changes associated with intrinsic aging andthe damages caused by extrinsic factors include thinning of hair andnail plate; lack of lubricants and luster, and uneven surface of hairand nails; fragility and splitting of hair and nails; and reduction offlexibility, resiliency, and elasticity of hair and nails.

The conventional management of signs of aging skin has been the use ofcosmetics, as well as medical procedures such as phenol, trichloroaceticacid, and other chemical peels, and plastic surgery, etc. Such medicalprocedures are costly and risky with serious side effects, and thetreatments alter only the cosmetic appearance of the skin, without anysignificant modifications of the underlying aging process.

Topical application to the skin, hair or nails of a composition of thepresent invention is beneficial for various cosmetic conditions anddermatological disorders including those associated with intrinsicand/or extrinsic aging and extrinsic factors, and also including thosecharacterized by the foregoing changes to the skin, hair and nails.Exemplary indications are characterized as disturbed keratinization,defective syntheses of dermal components, and changes associated withaging of skin, nail and hair; and those indications which includedryness or loose of skin, nail and hair; xerosis; ichthyosis; palmar andplantar hyperkeratoses; uneven and rough surface of skin, nail and hair;dandruff; Darier's disease; lichen simplex chronicus; keratoses; acne;pseudofolliculitis barbae; irritation; dermatoses; eczema; psoriasis;itchy scalp and skin; pruritus; warts; herpes; age spots; lentigines;melasmas; blemished skin; mottled skin; hyperkeratoses; hyperpigmentedskin; abnormal or diminished syntheses of collagen, glycosaminoglycans,proteoglycans and elastin as well as diminished levels of suchcomponents in the dermis; stretch marks; skin lines; fine lines;wrinkles; thinning of skin, nail plate and hair; skin thickening due toelastosis of photoaging, loss or reduction of skin, nail and hairresiliency, elasticity and recoilability; lack of skin, nail and hairlubricants and luster; dull and older-looking skin, nail and hair;fragility and splitting of nail and hair; and other topical conditionsand indications.

(ii) Combination Compositions

In addition, compositions comprising one or more than oneoligosaccharide aldonic acid or related compound may also beincorporated into a composition comprising a cosmetic, pharmaceutical orother topical agent to enhance or create synergetic effects.

In accordance with this aspect of the invention, the compositions of thepresent invention may contain one or more oligosaccharide aldonic acidsor related compounds to magnify the therapeutic effect of an unrelatedcosmetic or pharmaceutical agent. At least one compound selected fromthe group consisting of oligosaccaride aldonic acids and relatedcompounds may be incorporated into composition containing a cosmetic orpharmaceutical agent for any of the uses described above. It has beenfound that such incorporation results in magnified therapeuticefficacies which are not simply additive effects.

Most pharmaceutical drugs produce their therapeutic effects by firstinteracting with their receptors in the target tissues. Many drugreceptors are functional macromolecules such as enzymes, cell membranecomponents or certain components of cells. The binding affinity orinteracting property of a drug toward its specific receptor molecule isintimately governed by the chemical structure of the drug. Since mostpharmaceutical agents are chemically different from oligosaccaridealdonic acids and related compounds of the instant invention, therespective receptor molecule should be different and so are thepharmacological actions and the therapeutic effects. Under suchconditions if an oligosaccharide aldonic acid and/or related compound isincorporated into a composition containing a pharmaceutical agent, oneof the following two consequences may arise:

(a) No enhancement or any substantial changes in either effect. In thiscase, the overall clinical effect would be a mixed effect, i.e. theeffect due to the pharmaceutical agent alone mixed with the effect dueto the oligosaccharide aldonic acid and/or related compound alone. Alsoin this case, the interaction between the pharmaceutical agent and itsreceptor molecule is not affected nor interfered by the presence ofoligosaccharide aldonic acid and/or related compound. Nor does theoligosaccharide aldonic acid and/or related compound assist in orenhance the binding affinity or the interaction of the pharmaceuticalagent toward its receptor molecule. The clinical results from suchcombination composition would be just the mixed effects.

(b) Amplified therapeutic action or substantial loss of therapeuticaction in either effect. In this case, the interaction between thepharmaceutical agent and its receptor molecule is affected eitherpositively or negatively by the presence of an oligosaccharide aldonicacid and/or related compound. From the point of positive effect, theoligosaccharide aldonic acid and/or related compound may produce anamplified effect by either increasing the affinity of the receptormolecule toward the pharmaceutical agent, acting as a better and moreefficient coenzyme or as an activator by disrupting barriers andremoving obstacles for better binding of the agent toward its receptormolecule; for example, enzyme activation by removal of naturalinhibitors. In all these cases the overall clinical results would be dueto magnified therapeutic effects which are not predictable from eithereffect alone.

From the point of negative effect, an oligosaccharide aldonic acid orrelated compound might interfere with or decrease the binding affinityof the pharmaceutical agent toward its receptor molecule; i.e., actingas an competitor or inhibitor. In such case, the overall clinicalresults should be due to substantial diminishment or completely loss oftherapeutic effects, which is also unpredictable from either effectalone.

At present we do not know the exact mechanism involved in thesynergistic effect or unexpected increase in therapeutic effect of acosmetic or dermatological agent by an oligosaccharide aldonic acid. Thefollowing are relevant observations.

(1) Not due to enhanced penetration.

The enhanced and substantial increase in therapeutic effects of acosmetic or dermatological agent incorporated with an oligosaccharidealdonic acid is not simply due to an increased penetration of thetopical agent into the skin, nor due to a simple addition or combinationeffects.

(2) Re-activation from therapeutic non-responsiveness.

Tachyphylaxis or so-called “drug resistance” is frequently encounteredwith corticosteroid or other drug therapy for topical treatment ofpsoriasis, eczema etc. On continued topical use, many patients developtachyphylaxis to corticosteroids, and the lesions very often do notrespond any more to topically applied corticosteroid compositions, evenunder occlusive dressings to enhance penetration. The exact nature ofsuch resistance to the drug is not known. One of the proposed hypothesesis that the available level of receptor molecule(s) for corticosteroidsin the skin is diminished or exhausted completely due to continued dailyuse of the drugs. However, it is not known whether the receptor level isreally low or the active site of the receptor molecule is covered-up byan inhibitor.

When tachyphylaxis is encountered from corticosteroid alone therapy,incorporation of an oligosaccharide aldonic acid into the corticosteroidcomposition would eradicate the drug resistance. If desired, thecomposition containing an oligosaccharide aldonic acid alone may beapplied alternatively with the corticosteroid therapy.

(3) Eradication of rebound worsening.

One well-known side effect associated with continued use of certaindrugs, such as corticosteroids, is a rebound worsening of the disease ifthe treatment is discontinued. The mechanism of worsening is not known.It has been speculated that the antiinflammatory property ofcorticosteroids is to suppress the immunological expression of thedisease. The disease process is not eradicated nor substantiallymodified, but is only held-up like river water is held-up by a dam.Discontinuation of the therapy is like removing the dam.

To prevent rebound worsening encountered with corticosteroids is toincorporate an oligosaccharide aldonic acid into the compositioncontaining a corticosteroid, or to use the oligosaccharide aldonic acidalternately with the corticosteroid.

(4) Prevention or eradication of side-effects.

Other well-known side effects associated with continued topical use of acorticosteroid are thinning and atrophy of the skin. To prevent oreliminate such side effects, an oligosaccharide aldonic acid may beincorporated into the composition containing a corticosteroid, or may beused alternately with the corticosteroid.

We have found that, in most cases, therapeutic effects of cosmetic andpharmaceutical agents are amplified when an oligosaccharide aldonic acidor related compound is incorporated into the composition, i.e.,consequence (b) above is observed.

The cosmetic and pharmaceutical agents which may be actuated byoligosaccharide aldonic acids and related compounds include those thatimprove or eradicate age spots, keratoses and wrinkles; local analgesicsand anesthetics; antiacne agents; antibacterials; antiyeast agents;antifungal agents; antiviral agents; antidandruff agents; antidermatitisagents; antihistamine agents; antipruritic agents; antiemetics;antimotionsickness agents; antiinflammatory agents; antihyperkeratolyticagents; antiperspirants; antipsoriatic agents; antiseborrheic agents;hair conditioners and hair treatment agents; antiaging and antiwrinkleagents; sunblock and sunscreen agents; skin lightening agents;depigmenting agents; vitamins; corticosteroids; tanning agents;humectants; hormones; retinoids; gum disease or oral care agents;topical cardiovascular agents; corn, callus and wart removing agents;dipilating agents; and other dermatologicals.

Some examples of cosmetic and pharmaceutical agents are aclovate,acyclovir, acetylsalicylic acid, adapalene, albuterol, aluminum acetate,aluminum chloride, aluminum hydroxide, aluminum chlorohydroxide,amantadine, aminacrine, aminobenzoic acid (PABA), aminocaproic acid,aminosalicylic acid, amitriptyline, anthralin, ascorbic acid, ascorylpalimate, atropine, azelaic acid, bacitracin, bemegride, beclomethasonedipropionate, benzophenone, benzoyl peroxide, betamethasonedipropionate, betamethasone valerate, brompheniramine, bupivacaine,butoconazole, calcipotriene, camphor, capsaicin, carbamide peroxide,chitosan, chlorhexidine, chloroxylenol, chlorpheniramine, ciclopirox,clemastine, clindamycin, clioquinol, clobetasol propionate,clotrimazole, coal tar, cromolyn, crotamiton, cycloserine,dehydroepiandrosterone, desoximetasone, dexamethasone, diphenhydramine,doxypin, doxylamine, dyclonine, econazole, erythromycin, estradiol,ethinyl estradiol, fluocinonide, fluocinolone acetonide, 5-fluorouracil,griseofulvin, guaifenesin, haloprogin, hexylresorcinol, homosalate,hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate,hydrocortisone 17-butyrate, hydrogen peroxide, hydroquinone,hydroquinone monoether, hydroxyzine, ibuprofen, ichthammol, imiquimod,indomethacin, ketoconazole, ketoprofen, kojic acid, lidocaine,meclizine, meclocycline, menthol, mepivacaine, methyl nicotinate, methylsalicylate, metronidazole, miconazole, minocycline, minoxidil,monobenzone, mupirocin, naftifine, naproxen, neomycin, nystatin, octylmethoxycinnamate, octyl salicylate, oxybenzone, oxiconazole,oxymetazoline, padimate O, permethrin, pheniramine, phenol,phenylephrine, phenylpropanolamine, piperonyl butoxide, podophyllin,podofilox, povidone iodine, pramoxine, prilocalne, procaine,promethazine propionate, propranolol, pseudoephedrine, pyrethrin,pyrilamine, resorcinol, retinal, 13-cis retinoic acid, retinoic acid,retinol, retinyl acetate, retinyl palmitate, salicylamide, salicylicacid, selenium sulfide, shale tar, sulconazole, sulfur, sulfadiazine,tazarotene, terbinafine, terconazole, tetracaine, tetracycline,tetrahydrozoline, thymol, tioconazole, tolnaftate, triamcinolonediacetate, triamcinolone acetonide, triamcinolone hexacetonide,triclosan, triprolidine, undecylenic acid, urea, vitamin E acetate, woodtar, and zinc pyrithione.

Another example of cosmetic or other agents that may be combined withone or more oligosaccharide aldonic acids and related compounds includehydroxyacids, ketoacids and related compounds. Examples of hydroxy acidsinclude hydroxymonocarboxylic acids, hydroxydicarboxylic acids,2-hydroxycarboxylic acids, other hydroxycarboxylic acids,2-ketocarboxylic acids and related compounds. See, for example, U.S.Pat. Nos. 5,422,370, 5,547,988, 5,470,880, and 5,385,938. The hydroxyacids may exist as a free acid, an ester, a lactone, in salt form withan organic base or an inorganic alkali, and as stereoisomers.Representative examples of hydroxy acids and related compounds includeglycolic acid, mandelic acid, lactic acid, tropic acid, methyllacticacid, tartaric acid, citric acid, glucuronic acid, ribonic acid,gluconolactone, ribonolactone, gycolyl glycollate, lactyl lactate,trilactic acid and polylactic acid.

Yet another example of cosmetic or other agents that may be combinedwith one or more oligosaccharide aldonic acids or related compoundsinclude phenyl alpha acyloxyalkanoic acids and derivatives thereof.These compounds may exist in a free acid, or salt form, or asstereoisomers. See, for example, U.S. Pat. Nos. 5,258,391 and 5,643,949.Representative example of such compounds include diphenyl alphaacetoxyacetic acid, phenyl alpha acetoxyacetic acid, phenyl alpha methylalpha acetoxyacetic acid, phenyl alpha acetoxypropanoic acid, and2-phenyl beta acetoxypropanoic acid.

Still another example of cosmetic or other agents that may be combinedwith one or more oligosaccharide aldonic acids or related compoundsinclude N-acetyl-aldosamines, N-acetylamino acids and related N-acetylcompounds. These compounds may exist in a free acid, lactone or saltform, or as stereoisomers. See, for example, U.S. patent applicationSer. No. 09/227,213, filed Jan. 8, 1999, now U.S. Pat. No. 6,159,485.Representative example of such compounds include N-acetyl-glucosamineand N-acetyl-proline.

When the compositions according to the present invention are used forgeneral care, moisturizing, dry skin, skin smoothing and itchy skin, aswell as for treatment and prevention, of various cosmetic conditions anddermatological disorders, including those associated with intrinsicand/or extrinsic aging, as well as with changes or damage caused byextrinsic factors, examples of suitable cosmetic or other agents thatmay be combined with one or more oligosaccharide aldonic acids orrelated compounds include: hydroxyacids, ketoacids and relatedcompounds; phenyl alpha acyloxyalkanoic acids and derivatives thereofN-acetyl-aldosamines, N-acetylamino acids and related N-acetylcompounds; those that improve or eradicate age spots, keratoses andwrinkles; local analgesics and anesthetics; antiacne agents;antibacterials; antiyeast agents; antifungal agents; antiviral agents;antidandruff agents; antidermatitis agents; antihistamine agents;antipruritic agents; antiemetics; antimotionsickness agents;antiinflammatory agents; antihyperkeratolytic agents; antiperspirants;antipsoriatic agents; antiseborrheic agents; astringents; cleansingagents; hair conditioners and hair treatment agents; antiaging andantiwrinkle agents; sunblock and sunscreen agents; skin lighteningagents; depigmenting agents; vitamins; corticosteroids; tanning agents;hormones; retinoids; topical cardiovascular agents; corn, callus andwart removing agents; and other dermatologicals.

Some examples of cosmetic and pharmaceutical agents are aclovate,acyclovir, acetylsalicylic acid, adapalene, albuterol, aluminum acetate,aluminum chloride, aluminum hydroxide, aluminum chlorohydroxide,amantadine, aminacrine, aminobenzoic acid (PABA), aminocaproic acid,aminosalicylic acid, amitriptyline, anthralin, ascorbic acid, ascorylpalimate, atropine, azelaic acid, bacitracin, bemegride, beclomethasonedipropionate, benzophenone, benzoyl peroxide, betamethasonedipropionate, betamethasone valerate, brompheniramine, bupivacaine,butoconazole, calcipotriene, camphor, capsaicin, carbamide peroxide,chitosan, chlorhexidine, chloroxylenol, chlorpheniramine, ciclopirox,clemastine, clindamycin, clioquinol, clobetasol propionate,clotrimazole, coal tar, cromolyn, crotamiton, cycloserine,dehydroepiandrosterone, desoximetasone, dexamethasone, diphenhydramine,doxypin, doxylamine, dyclonine, econazole, erythromycin, estradiol,ethinyl estradiol, fluocinonide, fluocinolone acetonide, 5-fluorouracil,griseofulvin, guaifenesin, haloprogin, hexylresorcinol, homosalate,hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate,hydrocortisone 17-butyrate, hydrogen peroxide, hydroquinone,hydroquinone monoether, hydroxyzine, ibuprofen, ichthammol, imiquimod,indomethacin, ketoconazole, ketoprofen, kojic acid, lidocaine,meclizine, meclocycline, menthol, mepivacaine, methyl nicotinate, methylsalicylate, metronidazole, miconazole, minocycline, minoxidil,monobenzone, mupirocin, naftifine, naproxen, neomycin, nystatin, octylmethoxycinnamate, octyl salicylate, oxybenzone, oxiconazole,oxymetazoline, padimate O, permethrin, pheniramine, phenol,phenylephrine, phenylpropanolamine, piperonyl butoxide, podophyllin,podofilox, povidone iodine, pramoxine, prilocalne, procaine,promethazine propionate, propranolol, pseudoephedrine, pyrethrin,pyrilamine, resorcinol, retinal, 13-cis retinoic acid, retinoic acid,retinol, retinyl acetate, retinyl palmitate, salicylamide, salicylicacid, selenium sulfide, shale tar, sulconazole, sulfur, sulfadiazine,tazarotene, terbinafine, terconazole, tetracaine, tetracycline,tetrahydrozoline, thymol, tioconazole, tolnaftate, triamcinolonediacetate, triamcinolone acetonide, triamcinolone hexacetonide,triclosan, triprolidine, undecylenic acid, urea, vitamin E acetate, woodtar, and zinc pyrithione. Other examples of suitable cosmetic andpharmaceutical agents are well known to those of skill in the art.

When the compositions according to the present invention are used forgeneral care, as well as treatment and prevention of diseases andconditions, of the oral and vaginal mucosa, examples of suitablecosmetic or other agents that may be combined with one or moreoligosaccharide aldonic acids or related compounds include:hydroxyacids, ketoacids and related compounds; phenyl alphaacyloxyalkanoic acids and derivatives thereof N-acetyl-aldosamines,N-acetylamino acids and related N-acetyl compounds; local analgesics andanesthetics; antibacterials; antiyeast agents; antifungal agents;antiviral agents; antihistamine agents; antipruritic agents;antiemetics; antimotion sickness agents; antiinflammatory agents;vitamins; corticosteroids; hormones; and gum disease or oral careagents.

Some examples of cosmetic and pharmaceutical agents are clotrimazole,ketoconazole, miconazole, griseofulvin, econazole, metronidazole,hydroxyzine, diphenhydramine, pramoxine, lidocaine, procaine,mepivacaine, monobenzone, anthralin, coal tar, benzocaine, benzoylperoxide, erythromycin, tetracycline, clindamycin, meclocycline,hydroquinone, hydroquinone monoether, minocycline, naproxen, ibuprofen,theophylline, cromolyn, albuterol, retinol, retinyl acetate, retinylpalmitate, retinal, retinoic acid, 13-cis retinoic acid, hydrocortisone,hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone17-butyrate, betamethasone valerate, betamethasone dipropionate,triamcinolone acetonide, fluocinonide, clobetasol, propionate, benzoylperoxide, kojic acid, crotamiton, propranolol, promethazine, salicylicacid, vitamin E and vitamin E acetate. Other examples of suitablecosmetic and pharmaceutical agents are well known to those of skill inthe art.

When the compositions according to the present invention are used forgeneral oral care, as well as treatment and prevention of oral and gumdiseases, examples of suitable cosmetic or other agents that may becombined with one or more oligosaccharide aldonic acids or relatedcompounds include: hydroxyacids, ketoacids and related compounds; phenylalpha acyloxyalkanoic acids and derivatives thereofN-acetyl-aldosamines, N-acetylamino acids and related N-acetylcompounds; analgesics and anesthetics; antibacterials; antiyeast agents;antifungal agents; antiviral agents; antiinflammatory agents; vitamins;and other gum disease or oral care agents.

Some examples of cosmetic and pharmaceutical agents are triclosan,sodium flouride, zinc chloride, zinc citrate, zinc sulfate,chlorhexidine, chlorhexidine and digluconate.

When the compositions according to the present invention are used fortreating skin wounds, for example in aiding the healing of skin cuts,tears, lacerations, burns, punctures, and other wounds, examples ofsuitable cosmetic or other agents that may be combined with one or moreoligosaccharide aldonic acids or related compounds include:hydroxyacids, ketoacids and related compounds; phenyl alphaacyloxyalkanoic acids and derivatives thereof N-acetyl-aldosamines,N-acetylamino acids and related N-acetyl compounds; analgesics andanesthetics; wound cleansers; antibacterials; antiyeast agents;antifungal agents; antiviral agents; antiinflammatory agents; skinlightening agents; depigmenting agents; vitamins; burn relief agents;and corticosteroids.

(iii) Molecular Complex and Slow-Release Compositions

A formulation containing an oligosaccharide aldonic acid usually has apH of below 3.0, and the composition may irritate human skin of atopicor sensitive skin type on repeated topical application, due to lower pHor uncontrolled release and penetration of the acid into stratum corneumof the skin. We have found that an oligosaccharide aldonic acid can forma buffer system with an alkali and/or a molecular complex with acomplexing agent, and the resulting composition has the followingattributes: (1) easy and simple process in formulating, (2) raising theoverall pH of the formulation to above 3.0, (3) having a buffer systemin the composition, (4) no irritation or minimal stinging to sensitiveskin, (5) controlled or slow-release of the active ingredient into theskin, and (6) retaining the therapeutic efficacy. The substance used forneutralizing, partially neutralizing, salt forming, buffering orcomplexing may be an inorganic or organic alkali, or amphoteric.

An alkali is defined as a substance which shows a pH of above 7.0 in asolution. Common inorganic alkalis include for example ammoniumhydroxide, ammonium phosphate, ammonium carbonate or bicarbonate, sodiumhydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, sodiumphosphate, and the like alkalis formed from potassium, calcium,magnesium, strontium, aluminum, zinc, and lithium. Common organicalkalis are amines, hydroxylamines, imines, guanidines, amine oxides,alkanolamines, alkoxylated amines and alkylamido alkylamines, such asdiethanolamine, triethanolamine, isopropanolamine, diisopropanolamine,triisopropanolamine, aminobutanol, aminoethyl propanediol, aminomethylpropanol, aminomethyl propanediol, isopropylamine, methylethanol amine,diisopropylamine, dipropylenetriamine, glucamine, N-methylglucamine,morpholine, tromethamine, cocamines, soyamines, oleamines, stearamines,quaterniums and the like. The buffer system in the composition consistsof two species; namely oligosaccharide aldonic free acid andoligosaccharide aldonate anion despite an inorganic or organic alkali.

A molecular complexing agent with an oligosaccharide aldonic acid may bean amphoteric or non-amphoteric substance. The mole ratio of acomplexing agent may be higher than one, however the preferred ratio isless than one, and most preferred ratio is from 0.1 to 0.5. Theamphoteric substance by definition should have both an acidic and abasic functional groups in the molecule, and can behave both as an acidand an alkali in a solution. Inorganic amphoteric substances includecertain metallic oxides such as aluminum oxide and zinc oxide. However,the preferred amphoteric system consists of an organic amphotericsubstance. The molecule of an organic amphoteric substance shouldconsist of at least one acidic function selected from carboxylic,phosphoric and sulfonic groups, and at least one basic function fromamino, imino and guanido groups. Examples of organic amphotericsubstances include amino acids, peptides, polypeptides, proteins andrelated compounds such as glycine, arginine, lysine, cysteine, proline,glutamine, tryptophan, asparagine, tyrosine, ornithine, citrulline,creatine, histidine and canavanine.

In an amphoteric system, the molecular complex consists of several ionicspecies. For example, a triple ionic complex will be formed from onemole of an oligosaccharide aldonic acid (having one reactive group) withone mole of glycine (having two functional groups), and a quadrupleionic complex will be formed with arginine or lysine (having threefunctional groups). Due to ionic bonds and forces between the positivecharge and the negative charge of the molecular complex ions, therelease and penetration of the oligosaccharide aldonic acid into theskin will be controlled at moderate and optimal rate. Thus theslow-release system can reduce or eliminate skin irritation withoutcompromising the intended therapeutic effects.

The non-amphoteric complexing agents are organic alkalis which includeorganic amines, polyamines, hydroxylamines, imines, guanidines, amineoxides, alkanolamines, alkoxylated amines, alkylamido alkylamines, aminoacid esters, amino acid amides, aminosaccharides, aminoalditols,aminocyclitols, fattyamines, imidazolines and the like which are capableof forming the molecular complex and/or salts with oligosaccharidealdonic acids. The molecular weight of a complexing agent may range from50 to 10,000, however the preferred one ranges from 100 to 600. Examplesof some complexing agents include creatinine, glycine ethyl ester,arginine ethyl ester, lysine methyl ester, proline ethyl ester,citrulline benzyl ester, glycinamide, argininamide, prolinamide,lysinamide, glucamine, methylglucamine, glucosamines and glucosylamines,other glycosamines and glycosylamines, aminoinositols, chitosan,stearamidoethyl diethylamine, stearamidopropyl dimethylamine,stearamidoethyl diethanolamine, quaternary ammonium hydroxide.

(iv) Antioxidant Properties

An antioxidant may be defined as a substance capable of preventing orinhibiting oxidation. Most oligosaccharide aldonic acids are antioxidantcompounds because they possess two or more hydroxyl groups near thecarboxylic group. The antioxidant property is readily determined byusing any one of the following test methods: prevention or retardationof air oxidation of (a) anthralin, (b) hydroquinone, or (c) banana peel.A freshly prepared anthralin solution or cream is bright yellow, and anair oxidized one is brownish or black. A hydroquinone solution or creamis colorless or white color, and an air oxidized one is brownish orblack. A freshly peeled banana peel is light yellow in color and anoxidized one ranges in color from tan, dark tan, brown to brownishblack.

For example, in control experiments, fresh banana peels cut into sizesof 1×2 cm in 50 mm plastic petri dishes containing 5 ml water at neutralor acidic pH changed in color from white-yellowish to tan within 6 hoursat room temperature, and changed to dark tan color during the nextperiod of 24 to 72 hours. When fresh banana peels were placed in dishescontaining 5 ml of 0.1 M lactobionic acid under the same conditions, thebanana peels remained white-yellowish for the period of 24 hours, andchanged in color to tan after 72 hours. The above test results show thatlactobionic acid is an antioxidant substance. Using anthralin andhydroquinone test methods also confirmed that lactobionic acid is amoderate antioxidant.

(v) Gel Matrix Formation

In contrast to an alpha hydroxyacid and polyhydroxyacid, anoligosaccharide aldonic acid can form a gel matrix when its aqueoussolution is evaporated at room temperature. The transparent gel obtainedretains certain amount of water forming a clear gel matrix. The amountof water retention depends on individual oligosaccharide aldonic acid.Examples of gel matrix preparations are provided below.

The formation of a gel matrix between an oligosaccharide aldonic acidand water has been found to have moisturizing, soothing, healing andslow-release effects in addition to other various beneficial effects toskin, mucous membrane, hair and nail. The beneficial effects from anoligosaccharaide aldonic acid within the skin, nail and hair areexpected to include those provided by glycosaminoglycans (GAGs). This isdue to similarities in the basic chemical structure of oligosaccharaidealdonic acids and GAGs, and the fact that they both form a gel matrixwith water. Exemplary beneficial effects and functions of GAGs insidethe skin includes (i) binding with polycations and cations, such assodium and potassium ions, to enhance water retention, and (ii) specificinteraction with collagen, elastin, fibronectin, laminin and otherproteins to stabilize the turgor of the skin.

3. General Preparation of the Cosmetic and Therapeutic Compositions

(i) General Preparation

Compositions comprising an oligosaccharide aldonic acid or relatedcompound of the instant invention may be formulated as solution, gel,lotion, cream, ointment, shampoo, spray, stick, powder, masque, mouthrinse or wash, vaginal gel or preparation, or other form acceptable foruse on skin, nail, hair, oral mucosa, vaginal mucosa, mouth or gums.

To prepare a solution composition, at least one oligosaccharide aldonicacid or related compound of the instant invention is dissolved in asolution prepared from water, ethanol, propylene glycol, butyleneglycol, and/or other topically acceptable vehicle. The concentration ofa single oligosaccharide aldonic acids or related compound or the totalconcentration of all oligosaccharide aldonic acids and relatedcompounds, where the composition comprises more than one oligosaccharidealdonic acids or related compounds, may range from 0.01 to 99.9% byweight of the total composition, with preferred concentration of from0.1 to 50% by weight of the total composition and with more preferredconcentration of from 0.5 to 25% by weight of the total composition.Contemplated embodiments of the instant invention include ranges of 0.1%to 0.2%, 0.2% to 0.3%, 0.3% to 0.4%, 0.4% to 0.5%, 0.5% to 0.6%, 0.6% to0.7%, 0.7% to 0.8%, 0.8% to 0.9%, 0.9% to 1%, 1% to 2%, 2% to 3%, 3% to4%, 4% to 5%, 5% to 6%, 6% to 7%, 7% to 8%, 8% to 9%, 9% to 10%, 10% to14%, 14% to 18%, 18% to 22%, 22% to 26%, 26% to 30%, 30% to 35%, 35% to40%, 40% to 45%, 45% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% nto 90%, and 90% to 99.9% by weight of the total composition.

To prepare a topical composition in lotion, cream or ointment form, theoligosaccharide aldonic acid or related compounds is first dissolved inwater, ethanol, propylene glycol, and/or another vehicle, and thesolution thus obtained is mixed with a desired base or pharmaceuticallyacceptable vehicle to make lotion, cream or ointment. Concentrations ofthe oligosaccharide aldonic acid or related compounds are the same asdescribed above.

A topical composition of the instant invention may also be formulated ina gel or shampoo form. A typical gel composition is formulated by theaddition of a gelling agent such as chitosan, methyl cellulose, ethylcellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer orammoniated glycyrrhizinate to a solution comprising the oligosaccharidealdonic acid or related compound. The preferred concentration of thegelling agent may range from 0.1 to 4 percent by weight of the totalcomposition. In the preparation of shampoo, the oligosaccharide aldonicacids or related compounds is first dissolved in water or propyleneglycol, and the solution thus obtained is mixed with a shampoo base.Concentrations of the oligosaccharide aldonic acids or related compoundsused in gel or shampoo form are the same as described above.

To prepare a combination composition for synergetic effects, a cosmetic,pharmaceutical or other topical agent is incorporated into any one ofthe above compositions by dissolving or mixing the agent into theformulation.

Other forms of compositions for delivery of oligosaccharide aldonicacids and related compounds of the instant invention are readilyblended, prepared or formulated by those skilled in the art.

(ii) Gel Matrix Preparations

In contrast to an alpha hydroxyacid and polyhydroxyacid, anoligosaccharide aldonic acid can form a gel matrix. A gel matrix may beformed on the skin, hair, nail or mucosa when a solution comprising anoligosaccharide aldonic acid undergoes evaporation.

In one example, a gel matrix can be formed when aqueous solutioncomprising an oligosaccharide aldonic acid is evaporated at roomtemperature. The transparent gel thus obtained retains certain amount ofwater forming a clear gel matrix. The amount of water retention dependson individual oligosaccharide aldonic acid. For example, maltobionicacid 1 g in a beaker was dissolved in water 1 ml, and the solution thusobtained was left at room temperature. Fifty percent of the originalwater had been evaporated at the end of 24 hours, and 57% at the end of48 hours, and 60% at the end of 72 hours, and no more or minimalevaporation of water could be detected after 72 hours. A clear gel filmthus obtained contained 29% water complexed with maltobionic acidmolecules. In the same manner, lactobionic acid formed a clear gelmatrix with 14% water molecules and cellobionic acid formed atransparent gel with 7% water molecules. The formation of a gel matrixbetween an oligosaccharide aldonic acid and water has been found to havesoothing, healing and slow-release effects in addition to other variousbeneficial effects to skin, mucous membrane, hair and nail.

The following are illustrative examples of formulations and otheraspects of the present invention. Although the examples utilize onlyselected compounds and formulations, it should be understood that thefollowing examples are illustrative and not limiting. Therefore, any ofthe aforementioned oligosaccharide aldonic acids or related compoundsmay be substituted according to the teachings of this invention in thefollowing examples.

Example 1

A typical experiment to determine a gel matrix formation of anoligosaccharide aldonic acid may be carried out as follows.

Maltobionic acid 1 g in a beaker of 3.6 cm diameter and 3.6 cm heightwas dissolved in water 1 ml, and the solution thus obtained was left atroom temperature between 20-25° C. to allow a slow evaporation of thewater. Fifty percent of original water had been evaporated at the end of24 hours, 57% at the end of 48 hours, 60% at the end of 72 hour and60.5% at the end of 96 Hours. A clear continuous gel film was formed atthe end of 72 hours, and this was confirmed by observation under amicroscope and determination from its physical characteristics. Thecontinuous transparent film thus obtained consisted of 71% maltobionicacid and 29% water by weight, and was formed as a complex gel matrixbetween maltobionic acid molecules and water molecules.

Under the same conditions, a clear continuous gel film was formed fromlactobionic acid 1 g and water 1 ml. The continuous film thus obtainedconsisted of 86% lactobionic acid and 14% water by weight, and wasformed as a complex gel matrix between lactobionic acid molecules andwater molecules.

Under the same experiment, a clear continuous gel film was formed fromcellobionic acid 1 g and water 1 ml. The continuous film thus obtainedconsisted of 93% cellobionic acid and 7% water by weight, and was formedas a complex gel matrix between cellobionic acid molecules and watermolecules.

Under the same conditions and experiment, gluconic acid did not form anyform of a gel matrix.

Example 2

Antioxidant property of an oligosaccharide aldonic acid may bedetermined by utilizing anthralin test method as follows.

Anthralin also known as dithranol is a yellowish powder, and acomposition containing anthralin without a suitable antioxidant ischemically unstable even at room temperature. For example, anthralin0.05% in an oil-in-water cream changed in color from yellow to graywithin 24 hours at room temperature, and the cream became brownishwithin 48 hours. Under anhydrous condition, anthralin 0.05% ointmentprepared from white petrolatum 2 parts and mineral oil 1 part by weightchanged in color from bright yellow to grayish yellow within 24 hours,and the ointment became brownish after 12 days at room temperature.

Based on the above observations, an oil-in-water cream containing 0.4%anthralin with or without a known antioxidant was used as a positive orvehicle control. The final concentration of a test substance orantioxidant was 0.1 M. It was found that while the control cream withoutan antioxidant changed in color from yellow to grey within 24 hours, thepositive control cream with a known antioxidant (vitamin C or oxalicacid) and the test cream containing lactobionic acid, maltobionic acidor cellobionic acid did not change the color within 24 hours. Theseresults indicated that the bionic acids are comparably equal to vitaminC and oxalic acid as antioxidant substances.

Example 3

Antioxidant property of an oligosaccharide aldonic acid may also bedetermined by utilizing hydroquinone test method as follows.Hydroquinone also known as 1,4-dihydroxybenzene is a white powder, and acomposition containing hydroquinone without a suitable antioxidant ischemically unstable even at room temperature. For example, hydroquinone2% in an oil-in-water cream changed in color from white to grey within 2hours, and the cream became light brown within 48 hours and dark brownafter 72 hours at room temperature. Under the same test conditions, thecream containing 2% hydroquinone and 0.4 M concentration of a knownantioxidant (vitamin C, citric acid or N-acetylcysteine), maltobionicacid, lactobionic acid or cellobionic did not change color even after 5days. These results indicated that the bionic acids are comparably equalto vitamin C, citric acid and N-acetylcysteine as antioxidantsubstances.

Example 4

Antioxidant property of an oligosaccharide aldonic acid may also bedetermined by utilizing banana peel test method as follows.

A fresh ripe banana peel cut into sizes of 2×2 cm has the outer layerlight yellow in color. These freshly cut banana peels after exposed toair or immersed in an aqueous solution without an antioxidant in 50 mmplastic petri dishes rapidly changed in color from yellowish to tanwithin 3 hours, dark tan within 24 hours and brown black after 72 hours.A test substance including a positive control such as vitamin C, citricacid or N-acetylcysteine was prepared as 0.1 M concentration, and eachtest dish contained 5 ml test solution. Freshly cut banana peels 2×2 cmin sizes were immersed in 5 ml test solutions including knownantioxidants and vehicle controls with pH at 7.0 and 4.0. It was foundthat while the banana peels immersed in water alone changed in colorfrom white yellowish to tan within 4 hours, the banana peels did notchange color in the solution containing maltobionic acid or lactobionicacid. The same results were also found for the known antioxidantsubstances; vitamin C, citric acid and N-acetylcysteine. These resultsindicated that the bionic acids are antioxidant substances.

Example 5

Typical solution compositions suitable for topical use on hair, scalp,nail or skin, or use for wound healing, or for general care of oral orvaginal mucosa comprising an oligosaccharide aldonic acid may beformulated as follows.

(a) Maltobionic acid 50% aqueous solution was prepared by dissolvingmaltobionic acid 50 g in 50 ml water. This solution 10 g was mixed witha vehicle 90 ml prepared from ethanol 40 parts, water 40 parts andpropylene glycol 20 parts by volume. The composition had pH 3.1 andcontained 5% maltobionic acid.

(b) Cellobionic acid 25% aqueous solution was prepared by dissolvingcellobionic acid 25 g in 75 ml water. This solution 40 g was mixed witha vehicle 60 ml prepared from ethanol 40 parts, water 40 parts andpropylene glycol 20 parts by volume. The composition had pH 3.5 andcontained 10% cellobionic acid.

(c) Lactobionic acid 0.5 g was dissolved in 99.5 ml solution preparedfrom water 40 parts, ethanol 40 parts and propylene glycol 20 parts byvolume. The composition had pH 2.6 and contained 0.5% lactobionic acid.

A solution composition with pH 1.9 containing 10% lactobionic acid wasformulated from 10 g lactobionic acid dissolved in water 50 ml, ethanol20 ml and propylene glycol 20 ml.

A solution composition with pH 2.1 containing 25% lactobionic acid wasformulated from lactobionic acid 50% aqueous solution 50 g and enoughethanol to make a total volume of 100 ml.

Example 6

Typical shampoo compositions comprising an oligosaccharide aldonic acidfor hair, scalp or body wash may be formulated as follows.

Maltobionic acid 50% aqueous solution 10 g was mixed uniformly with ashampoo base 90 g. The composition had pH 2.9 and contained 5%maltobionic acid.

Cellobionic acid 25% aqueous solution 20 g was mixed uniformly with ashampoo base 80 g. The composition had pH 3.9 and contained 5%cellobionic acid.

Lactobionic acid 10 g was dissolved in 20 ml water, and the solutionthus obtained was mixed uniformly with a shampoo base 70 g. Thecomposition had pH 2.6 and contained 10% lactobionic acid.

Example 7

Typical cream compositions comprising an oligosaccharide aldonic acidfor cosmetic or dermatological indications, or for general care of nail,skin or mucous membranes may be formulated as follows.

Maltobionic acid 50% aqueous solution 50 g was mixed with anoil-in-water base 50 g. The composition had pH 1.7 and contained 25%maltobionic acid.

Cellobionic acid 25% aqueous solution 20 g was mixed with anoil-in-water base 80 g. The composition had pH 3.3 and contained 5%cellobionic acid.

Lactobioic acid 2 g was dissolved in 18 ml water, and the solution thusobtained was mixed uniformly with a cream base 80 g or commerciallyavailable hydrophilic ointment. The white cream thus formulated had pH2.2 and contained 2% lactobionic acid.

A cream composition with pH 1.7 contained 10% lactobionic acid wasformulated from lactobionic acid 10 g, water 10 ml and cream base 80 g.

A cream composition with pH 1.8 contained 18% lactobionic acid wasformulated from lactobionic acid 54% aqueous solution 33.3 g and a creambase 66.7 g.

A cream composition with pH 1.7 contained 27% lactobionic acid wasformulated from lactobionic acid 54% aqueous solution 50 g and a creambase 50 g.

Example 8

Typical gel compositions comprising an oligosaccharide aldonic acid forcosmetic or dermatological indications, wound healing, or for generalcare of hair, scalp, nail, skin, oral or vaginal mucosa may beformulated as follows.

Maltobionic acid 50% aqueous solution 20 g was mixed uniformly with agel base 80 g. The composition had pH 2.9 and contained 10% maltobionicacid.

Cellobionic acid 6 g was dissolved in water 18 ml, and the solution thusobtained was mixed with a gel base 76 g. The composition had pH 3.9 andcontained 6% cellobionic acid.

Lactobionic acid 54% aqueous solution 9.3 g was mixed uniformly with agel base 90.7 g. The gel composition thus formulated had pH 3.0 andcontained 5% lactobionic acid.

Example 9

Typical water-in-oil compositions comprising an oligosaccharide aldonicacid for cosmetic or dermatological indications, wound healing, or forgeneral care of nail, skin, oral or vaginal mucosa may be formulated asfollows.

Maltobionic acid 50% aqueous solution 20 g was mixed uniformly with awater-in-oil base 80 g. The water non-washable composition thusformulated contained 10% maltobionic acid.

Cellobionic acid 25% aqueous solution 20 g was mixed uniformly with awater-in-oil base 80 g. The water non-washable composition thusformulated contained 5% cellobionic acid.

Example 10

Typical masque compositions comprising an oligosaccharide aldonic acidfor cosmetic or dermatological indications of nail, or skin for exampleon the face, may be formulated as follows.

Maltobionic acid 50% aqueous solution 16 g was mixed uniformly with amasque base 84 g. The masque composition thus formulated contained 8%maltobionic acid.

Cellobionic acid 25% aqueous solution 36 g was mixed uniformly with amasque base 64 g. The masque composition thus formulated contained 8%cellobionic acid.

Example 11

A typical synergetic composition comprising an oligosaccharide aldonicacid in combination with an anti-fungal agent for infections of nail,scalp, hair, skin, oral or vaginal mucosa may be formulated as follows.

Lactobionic acid 10 g was dissolved in 90 ml solution prepared fromwater 40 ml, ethanol 40 ml and propylene glycol 20 ml. The compositionthus formulated contained 10% lactobionic acid, and was used as a nailor scalp conditioner.

For fungal infections, lactobionic acid 10 g and clotrimazole 2 g weredissolved in 88 ml solution prepared from water 60 ml, ethanol 20 ml andpropylene glycol 20 ml. The synergetic composition thus formulated hadpH 3.3 and contained 10% lactobionic acid and 2% clotrimazole, and weresuitable for treatment of fungal infections of nail, scalp, hair, skin,oral or vaginal mucosa.

Example 12

A typical synergetic composition comprising an oligosaccharide aldonicacid in combination with a corticosteroid for eczema, psoriasis or otherinflammatory dermatoses may be formulated as follows.

Lactobionic acid 5 g was dissolved in 10 ml water, and hydrocortisone17-valerate 0.2 g was dissolved in 10 ml warm propylene glycol. Twosolutions thus prepared were added to and mixed uniformly with 74.8 gcream base or commercially available hydrophilic ointment. The whitecream thus formulated contained 5% lactobionic acid and 0.2%hydrocortisone 17-valerate.

Example 13

A typical synergetic composition comprising an oligosaccharide aldonicacid in combination with an anti-acne agent may be formulated asfollows.

Lactobionic acid 54% aqueous solution 11 g and salicylic acid 2 g weredissolved and mixed with 87 ml solution prepared from ethanol 70 ml andpropylene glycol 30 ml. The synergetic composition thus formulated hadpH 3.1, and contained 6% lactobionic acid and 2% salicylic acid.

Example 14

In one of the studies related to skin changes associated with aging,skin thickness was measured by micrometer calipers as follows:

The skin was grasped with a 2×6 cm metal hinge; the internal faces ofwhich were coated with emery cloth to prevent slippage, and manuallysqueezed to threshold subject discomfort. Combined thickness of twowhole-skin layers including thickness of the two hinge leaves wasmeasured with micrometer calipers. Thickness of the two hinge leaves wassubtracted to determine the actual thickness of two whole-skin layers.Triplicate measurements on treated sites were done and an average numberwas used for calculation of the skin thickness.

Example 15

A female subject, age 56, topically applied twice daily to her leftforearm for four weeks lactobionic acid 22% in a solution prepared fromwater 7 parts and propylene glycol 3 parts. After four weeks her rightforearm was still loose and relatively thin, and the skin was relativelyrough and dry. In contrast, her left forearm was more firm and plump,and the skin was smooth, soft and not dry. While there was no change inskin thickness of her right forearm, her left forearm had increased 12%in skin thickness as measured by the micrometer calipers described inthe Example. These results indicated that lactobionic acid would betopically effective and beneficial for various cosmetic anddermatological indications.

Example 16

A male subject, age 66, with chronic atopic eczema and pruritic dry skintopically applied twice daily maltobionic acid 17% cream to itchy skinareas of eczema and dry skin lesions for two weeks. The treated skinbecame smooth and less dry and itchy within a week of topicalapplication. The eczema lesions improved significantly after two weeksof topical treatment with maltobionic acid.

Example 17

A female subject, age 59, having xerosis with flaky dry skin conditionof her forearms topically applied twice daily maltobionic acid 5%water-in-oil cream for two weeks. After two weeks, her forearms becamesmooth and soft, and the dry skin condition disappeared completely.

Example 18

A male subject, age 60, having two skin fissures (open cuts) 2-3 mm longat the finger tips, extending from the hyponychia, topically appliedtwice daily lactobionic acid 10% oil-in-water cream to one fissure forone week. The other fissure was treated with a vehicle control. Whilethe control site remained unhealed and painful, the skin treated withthe active cream healed rapidly, and the pain disappeared after a fewdays of topical application. After a week of topical treatment with theactive cream, the skin fissure healed completely while the control siteremained unhealed. This result indicated that the oligosacchardiealdonic acid would be topically effective for promoting wound healing ofthe skin.

Example 19

A typical composition comprising molecular complex of an oligosaccharidealdonic acid in amphoteric system may be formulated as follows.

Lactobionic acid 7.2 g (0.02 mole) was dissolved in 14.4 ml water, andthe solution containing 33.3% active ingredient had pH 1.9. L-Arginine0.88 g (0.005 mole) was added to the solution with stirring to formmolecular complex as shown by an increase in pH of the solution. Thecomplexing reaction was completed as indicated by no more increase in pHof the solution. The final pH of the solution was 3.4, and the solutionwas mixed with sufficient quantity of water-in-oil cream to make a totalcomposition of 100 g by weight. The water-non-washable cream thusformulated contained molecular complex of 7.2% lactobionic acid and0.88% L-arginine.

Example 20

A typical synergetic composition comprising molecular complex of anoligosaccharide aldonic acid in combination with skin lightening agentsmay be formulated as follows.

Maltobionic acid 50% aqueous solution 14.4 g was diluted with 7.2 mlwater, and the solution had pH 1.6. L-Lysine 1.16 g was added to formmolecular complex as shown by the increase of pH to 3.3. In anothercontainer, hydroquinone 2 g and kojic acid 1 g were dissolved in warmpropylene glycol 12 g, and this solution together with the abovemolecular complex solution were mixed with oil-in-water cream to make atotal composition of 100 g by weight. The synergetic cream thusformulated contained 2% hydroquinone and 1% kojic acid in molecularcomplex of 7.2% maltobionic acid and 1.2% L-lysine.

Example 21

A typical synergetic composition comprising vitamin A and vitamin E maybe formulated as follows.

Cellobionic acid 3 g was dissolved in water 16 ml and propylene glycol 4ml, and L-arginine 0.4 g was added to the solution with stirring to forman amphoteric complex. This complex and retinyl acetate 2 g andtocopheryl acetate 2 g were mixed with an oil-in-water cream to make atotal composition of 100 g by weight. The amphoteric composition thusformulated had pH 5.5, and contained 3% cellobionic acid, 2% vitamin Aand 2% vitamin E. This composition is topical effective for variouscosmetic and dermatological indications.

Example 22

Lactobionic acid 50% aqueous solution 10 g was diluted with 60 ml waterand 10 ml propylene glycol, and the solution had pH 2.1. L-Arginine 5%solution 20 g prepared from 8 parts water and 2 parts propylene glycolby volume was added to form molecular complex of amphoteric system asshown by the increase of pH to 3.3. The composition thus formulatedcontained 5% lactobionic acid in molecular complex with 1% L-arginine.

A male subject, age 67, having chronic gum disease of bleeding duringthe tooth brushing, used the above bionic acid complex composition twicedaily as a gurgling solution with at least one minute of contact time inoral cavity. No food or drink was taken for the next 30 minutes. Afterone week of such oral treatment with the bionic acid composition, thegum bleeding stopped or became less noticeable during the toothbrushing. This result suggests that the oligosacchardie aldonic acidwould be effective or beneficial for treatment of gum diseases.

Example 23

Lactobionic acid 50% aqueous solution 10 g was uniformly mixed with anoil-in-water base 80 g, and the cream thus obtained had pH 2.5.L-Arginine 5% solution 10 g prepared from 8 parts water and 2 partspropylene glycol by volume was added to form molecular complex ofamphoteric system as shown by the increase of pH to 3.1. The compositionthus formulated contained 5% lactobionic acid in molecular complex with0.5% L-arginine.

A female subject, age 60, having dry vaginal mucosa topically appliedthe above bionic acid cream twice daily to the affected areas of themucosa. After one week of topical applications, the dryness of vaginalmucosa disappeared completely and the mucosa became smooth and moist.This result suggests that the oligosaccharide aldonic acid would betherapeutically effective for topical treatment of dry vaginal mucosa.

Example 24

Lactobionic acid 54% aqueous solution 30 g was uniformly mixed with anoil-in-water base 60 g. The cream thus prepared had pH 2.0 and contained18% lactobionic acid.

A male subject, age 66, having a lasting scrotum and perineum itch aftereach time taking a shower topically applied the above bionic acid creamto the affected areas of the skin. The itch stopped immediately aftertopical application of the cream. This result suggests that theoligosaccharide aldonic acid would be therapeutically effective andbeneficial for topical treatment of senior itch or itch of unknowncauses.

Example 25

A sterile 22-gauge needle was held in the jaws of a surgical needleholder, and two linear wounds 1 cm in length and 0.5 mm in depth weremade on alchohol-swabbed left forearm of a healthy male subject, age 76.The wounds were swabbed dry with cotton balls. A control solutioncontaining 0.9% sodium chloride in distilled water was applied to onewound, and a test solution containing 2% lactobionic acid in distilledwater was applied to the other wound. Both wounds were covered with 3MTegaderm tapes for five days. At the end of one week, whereas thecontrol wound was not epithelialized, the test wound was healed withre-epithelialization. The erythema disappeared from both skin sites atthe end of nine days.

These test results showed that a bionic acid was topically effective forimproving wound healing.

Example 26

A sterile 4 mm skin biopsy punch was used to make two circular wounds0.5 mm in depth on alcohol-swabbed left forearm of a healthy malesubject, age 76. The wounds were swabbed dry with cotton balls. Acontrol solution containing 0.9% sodium chloride in distilled water wasapplied to one circular wound, and a test solution containing 2%lactobionic acid in distilled water was applied to the other circularwound. Both wounds were covered with 3M Tegaderm tapes for five days. Atthe end of one week, the control wound was not epithelialized and thetest wound was healed with re-epithelialization. The erythemadisappeared from both skin sites at the end of nine days.

These test results showed that a bionic acid was topically effective forimproving wound healing.

Example 27

A female subject, age 60, developed contact dermatitis or erythema onher face after topical applications of 20% unneutralized glycolic acidcream. She applied 5% partially neutralized lactobionic acid cream onthe left side of her face and a control cream on the right side of herface. Whereas the erythema persisted on the right side of her face, theskin on the left side of her face improved substantially and theerythema became less noticeable after three topical applications oflactobionic acid cream over the 24 hour period.

These results showed that a bionic acid was topically effective inreducing skin irritations caused by an external factor.

Example 28

A male subject, age 67, with sensitive skin developed acute erythema onhis both thighs after taking hot shower using alkaline soap. He applied3% partially neutralized maltobionic acid cream on his left thigh and acontrol cream on his right thigh. Whereas the erythema and itchpersisted on his right thigh, the erythema and itch disappeared within afew minutes after topical application of maltobionic acid cream.

These results showed that a bionic acid was topically effective inreducing skin irritations caused by an external factor.

The invention described herein may be embodied in other specific formswithout departing from the spirit or essential characteristics thereof.The specific embodiments previously described are therefore to beconsidered as illustrative of, and not limiting, the scope of theinvention. Additionally, the disclosure of all patents or patentapplication, including U.S. provisional application Ser. No. 60/141,624,and all publications cited above are expressly incorporated herein byreference in their entireties to the same extent as if each wereincorporated by reference individually.

We claim:
 1. A method for the treatment of cosmetic conditions ordermatological disorders comprising topically applying a compositioncomprising a therapeutically effective amount of lactobionic acid asfree acid, ester, salt, partial salt, lactone, stereoisomeric,non-stereoisomeric, saturated or unsaturated, straight or branchedchain, or cyclic form thereof, wherein the cosmetic condition ordermatological disorder is selected from the group of indicationsconsisting of dryness or looseness of skin, nail and hair; xerosis;ichthyosis; palmar and plantar hyperkeratoses; uneven and rough surfaceof skin, nail and hair; dandruff; Darier's disease; lichen simplexchronicus; keratoses; rosacea; pseudofolliculitis barbae; eczema;psoriasis; pruritus; warts; herpes, hyperkeratoses; stretch marks;thinning of nail plate and hair; fragility and splitting of nail andhair; wound-healing and treatment of skin wounds; general care as wellas treatment of diseases and conditions of oral, gum, vaginal and analmucosa.
 2. The method of claim 1, wherein the cosmetic condition ordermatological disorder is selected from the group of indicationsconsisting of dry skin, rosacea, eczema, stretch marks, andpseudofolliculitis barbae.
 3. The method of claim 2, wherein thecosmetic condition or dermatological disorder is dry skin.
 4. The methodof claim 2, wherein the cosmetic condition or dermatological disorder isrosacea.
 5. The method of claim 2, wherein the cosmetic condition ordermatological disorder is eczema.
 6. The method of claim 2, wherein thecosmetic condition or dermatological disorder is stretch marks.
 7. Themethod of claim 2, wherein the cosmetic condition or dermatologicaldisorder is pseudofolliculitis barbae.
 8. The method of claim 1, whereinthe composition further comprises a topically active agent selected fromthe group consisting of local analgesics and anesthetics; antiyeastagents; antifungal agents; antiviral agents; antidandruff agents;antidermatitis agents; antihistamine agents; antipruritic agents;antiemetics; antimotion sickness agents; antiinflammatory agents;antihyperkeratotic agents; antiperspirants; antipsoriatic agents;antiseborrheic agents; vitamins; corticosteroids; tanning agents;hormones; amino acids; dipeptides; tripeptides; oligopeptides;polypeptides; retinoids; wound healing agents; oral, vaginal and analcare or treatment agents; and gum disease treatment or care agents. 9.The method of claim 8, wherein the topically active agent is selectedfrom the group consisting of aclovate, acyclovir, adapalene, albuterol,aluminum acetate, aluminum chloride, aluminum hydroxide, aluminumchlorohydroxide, amantadine, aminacrine, γ-aminobutanoic acid,aminocaproic acid, amitriptyline, anserine, anthralin, ascorbic acid,ascoryl palmitate, atropine, azelaic acid, bacitracin, bemegride,beclomethasone dipropionate, benzocaine, betamethasone dipropionate,betamethasone valerate, brompheniramine, bupivacaine, butoconazole,calcipotriene, camphor, capsaicin, carbamide peroxide, carnosine,chitosan, chlorhexidine, chloroxylenol, chlorpheniramine, ciclopirox,clemastine, clioquinol, clobetasol propionate, clotrimazole, coal tar,cromolyn, crotamiton, cycloserine, dehydroepiandrosterone,desoximetasone, dexamethasone, diphenhydramine, doxypin, doxylamine,dyclonine, econazole, estradiol, ethinyl estradiol, fluocinonide,fluocinolone acetonide, 5-fluorouracil, glutathione, griseofulvin,guaifenesin, haloprogin, hexylresorcinol, homocarnosine, hydrocortisone,hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone17-butyrate, hydrogen peroxide, hydroxyzine, ibuprofen, ichthammol,imiquimod, indomethacin, ketoconazole, ketoprofen, lidocaine, meclizine,menthol, mepivacaine, methyl nicotinate, miconazole, minocycline,minoxidil, mupirocin, naftifine, naproxen, neomycin, nystatin, ophidine,ornithine, oxiconazole, oxymetazoline, permethrin, pheniramine, phenol,phenylephrine, phenylpropanolamine, piperonyl butoxide, podophyllin,podofilox, povidone iodine, polymyxins, pramoxine, prilocalne, procaine,promethazine propionate, propranolol, pseudoephedrine, pyrethrin,pyrilamine, resorcinol, retinol, retinyl acetate, retinyl palmitate,salicylamide, selenium sulfide, shale tar, sulconazole, sulfur,sulfadiazine, tazarotene, terbinafine, terconazole, tetracaine,tetrahydrozoline, thymol, tioconazole, tolnaftate, triamcinolonediacetate, triamcinolone acetonide, triamcinolone hexacetonide,triclosan, triprolidine, undecylenic acid, urea, vitamin E acetate, woodtar, and zinc pyrithione.